L1: Principles of Vet Toxicology (Martyniuk) Flashcards
dosimetry
the idea that “all substances are poisons and there is none which is not a poison. The right dose differentiates poison from remedy.” (idea of Paracelsus)
Diclofenac
an anti-inflammatory used in cattle
-vultures feed on cattle treated with Diclofenac –> kidney failure
how many manmade chemicals are potential toxins?
> 50,000
how many toxic plants?
> 800
toxic vs. toxicology vs. toxicant
toxic: poisonous
toxicology: science of poisons (concerned w/ ID, tx, and assessing risks of poisons)
toxicant: compound that causes toxicity (natural or man-made)
xenobiotic
foreign substance found within an organism
4 main factors influencing toxicity
1) Toxicant: structure, metabolism, elimination, size, charge (chem/biological properties)
2) Exposure: (dose, time exposed, route of exposure, conc.)
3) Subject: breed, age, health, species
4) Environment: temp, bioavailability, altitude, etc.
3 classifications of chemical interactions in toxicity
additive
antagonistic
synergism
dose-response relationship
central concept of toxicology; assumes a cause and effect relationship and that response is proportional to dose. Shape of curve is always sigmoidal
NOAEL
No observable adverse effect level: max. dose that causes no adverse effect
LOAEL
Lowest Observable Adverse Effect Level: min. dose that you can measure an effect.
LD50:
dose producing death in 50% of animals
Threshold dose:
min. dose to produce reaction; indicates there is “safe” dose
acute exposure
single dose exposure or several doses w/n 24hr
sub-acute/subchronic exposure
exposure over 7-90d
chronic exposure
protracted exposure (6mo-lifetime)
toxicokinetics
study of the movement and disposition of the toxicant in an organism (ADME)
- influenced by dose, physiochemical properties of the toxin/drug, species differences in physiological and biochemical chars.
- math. rep. of how a toxin gets into, moves about, and causes an effect on the body
Does exposure = dose?
NO
ADME
absorption, distribution, metabolism, excretion
major routes of excretion:
renal (urine), hepatic (bile), fecal, GIT
absorption
uptake of material from site of exposure; the amt. of material that enters the body
distribution
from blood to tissues
metabolism
enzymatic conversion
aka biotransformation: the biological conversion of a chemical compound (exogenous or endogenous) into a second compound, or metabolite
-requires enzyme catalysts (phase I or II)
-primary biochemical pathway of xenobiotic metabolism
elimination
excretion from body. Can follow first or zero order kinetics
-influenced by half-life (when 50% of the compound is degraded)
3 main routes of exposure
1) Lungs (pulmonary surfaces)
- uptake of vapors, gases, mists, particulates
2) Gut (dietary exp.)**
- influenced by pH of gut, rate of digestion, residence time of food, microflora of gut
3) Dermis**
- hydrophobic compounds can go through skin of animals
Order 6 common absorption routes from fastest to slowest:
IV Pulmonary IM IP Oral Cutaneous
which is absorbed faster: aspirin or pesticide?
aspirin
things that can affect drug distr.
solubility, protein binding, physical characteristics/health of animal, pH, charge of compound, transporters/receptors for a certain compound, etc.
what happens between applied dose and target organ dose?
applied dose –> absorption –> internal dose –> distribution –> target organ dose
central medium of distr. of chemical that target organs
blood
main sites of biotransformation reactions
liver and kidney
- have highest enzyme conc.
- blood flow
- high surface area
phase I enzymes
increase hydrophilicity of compounds by adding reacting groups such as hydroxyl, thiol, carboxyl via REDOX reactions
phase II enzymes
increase hydrophilicity of compounds even further by forming inactive conjugates with addition of acetate, glucoronic acid, glycine, glutathione, etc. Use PRIMARY CONJUGATION reactions.
- have more species differences than phase I enzymes
- bigger proteins than Phase I
Biotransformation can lead to:
- enhanced elimination (lipophylic to hydrophylic)
- detoxification
- sequestration
- redistribution
- activation
possible adverse effects of sequestration
body still holding onto the toxin. If sequestration pathway randomly stops working, you can get serious acute adverse effect.
bioactivation
making compound more toxic by metabolizing it
Ex: parathion (pesticide) –> oxidation –> paraoxon
*parathion is especially toxic to pregnant animals
cats deficient in which metabolism process?
glucuronidation
dogs deficient in which metabolism process?
acetylation
guinea pigs/rats deficient in which metabolism process?
N-hydroxylation
pigs deficient in which metabolism process?
sulfation
name 3 ex. of compounds that bioactivate
benzopyrene
aflatoxin (a fungus)
acetaminophen
acetaminophen metabolism
acetaminophen activated by cytochrome P450 (a phase I enzyme) to N-acetyl-p-Benzoquinoneimine, which causes oxidative stress in tissues and ROS formation.
name 3 P450 inhibitors
cimetidine
enrofloxacin
grapefruit juice
name a P450 inducer
ethanol
2013 top 10 toxins
1) prescription pharmaceuticals
2) insecticides
3) OTC drugs (NSAIDs)
4) household products
5) human foods
6) vet meds (i.e. ivermectin)
7) chocolate
8) rodenticides (i.e. Warfarin)
9) toxic plants
10) lawn products
First-order elimination
constant FRACTION of chemical eliminated (dose dependent). plasma drug concentration decreases linearly with time.
-most common form of elimination
Zero-order elimination
constant AMOUNT of chemical eliminated; typically means that processes are saturated.
- dose INDEPENDENT
- acetaminophen, alcohol
most pesticides have short/long half-lives
short. (ie. Fipronel). Usually present with acute exposure.
How do toxicants cause toxicity?
1) Cellular damage, resulting from free radical damage, inhibiton of energy production, disruption of enzyme function
- i.e. Acetaminophen, arsenic
2) Organ system dysfunction (not assoc. with specific cellular injury, but lethal to intact organism)
- i.e. Insecticides, rodenticides
